A direct causal link between hippocampal adult neurogenesis and hippocampal dependent learning and memory remains unknown. Animal models of FASD show decreased levels of hippocampal adult neurogenesis and impaired hippocampal dependent behavior. Exposure to exercise alone or succeeded by environmental complexity enhances levels of adult neurogenesis and mitigates behavioral deficits on hippocampal-dependent tasks that result from neonatal alcohol exposure. The long-term goal of this research program is to determine the functional significance of exercise and/or environment induced newly generated neurons in the improved performance on hippocampal dependent tasks exhibited in FASD mice. Preliminary data indicate that exercise can rescue cognitive deficits induced by prenatal alcohol exposure. Pilot data show that nestin-TK reduces neurogenesis in exercising animals to sedentary levels through expression of a viral thymidine kinase in neural progenitor cells. The objective of this application is to (1) develop better treatments that would aid in the recovering of lost cognitive functioning due to neonatal alcohol exposure; (2) understand the functional role of newly generated neurons in the dentate gyrus of both the healthy and the neonatally exposed to alcohol brain. The central hypothesis for this research proposal is that new neurons are required for the exercise and/or environment-induced rescue deficits in hippocampal dependent behavior in FASD animals. The rationale is that understanding the functional relationship between hippocampal adult neurogenesis and hippocampal behavioral deficits can provide the foundation for developing specific therapeutic interventions for FASD patients. In the first aim, the applicant will determine the most successful intervention from combinations of exercise and/or environment for enhancing adult neurogenesis and behavioral performance in a mouse fetal alcohol model. Next, the applicant will directly test the role of new neurons, generated by the most successful intervention, through a Nestin TK transgenic model as well as through an innovative transgenic optogenetic model in which newly generated neurons are temporarily inactivated then reactivated. The proposed research is significant because it will determine the extent to which newly generated neurons contribute to enhanced hippocampal behavior in both the damaged and the healthy brain. The proposed research is innovative because it uses cutting-edge wireless optoeletronic technology combined with a novel transgenic mouse line to temporarily inactivate new neurons. To our knowledge, nowhere else in the world are they making these unique optoelectronic devices, that feature tiny LEDs mounted to an ultra thin biocompatible membrane that allows wireless minimally invasive optoelectronic capabilities. Ultimately, results from this proposal have the potential to inform development of effective therapies for improving cognitive performance in FASD cases in the United States.